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Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice

The cAMP/protein kinase A pathway regulates methamphetamine (METH)‐induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) an...

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Autores principales: Bosse, Kelly E., Charlton, Jennifer L., Susick, Laura L., Newman, Brooke, Eagle, Andrew L., Mathews, Tiffany A., Perrine, Shane A., Conti, Alana C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049486/
https://www.ncbi.nlm.nih.gov/pubmed/26146906
http://dx.doi.org/10.1111/jnc.13235
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author Bosse, Kelly E.
Charlton, Jennifer L.
Susick, Laura L.
Newman, Brooke
Eagle, Andrew L.
Mathews, Tiffany A.
Perrine, Shane A.
Conti, Alana C.
author_facet Bosse, Kelly E.
Charlton, Jennifer L.
Susick, Laura L.
Newman, Brooke
Eagle, Andrew L.
Mathews, Tiffany A.
Perrine, Shane A.
Conti, Alana C.
author_sort Bosse, Kelly E.
collection PubMed
description The cAMP/protein kinase A pathway regulates methamphetamine (METH)‐induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) and striatal dopamine function were evaluated in mice lacking AC 1/8 (DKO) and wild‐type (WT) mice. Only 5 mg/kg METH induced an acute locomotor response in DKO mice, which was significantly attenuated versus WT controls. DKO mice showed a marked attenuation in the development and expression of METH‐induced behavioral sensitization across doses relative to WT controls. While basal and acute METH (5 mg/kg)‐evoked accumbal dialysate dopamine levels were similar between genotypes, saline‐treated DKO mice showed elevated tissue content of dopamine and homovanillic acid in the dorsal striatum (DS), reflecting dysregulated dopamine homeostasis and/or metabolism. Significant reductions in DS dopamine levels were observed in METH‐sensitized DKO mice compared to saline‐treated controls, an effect not observed in WT mice. Notably, saline‐treated DKO mice had significantly increased phosphorylated Dopamine‐ and cAMP‐regulated phosphoprotein levels, which were not further augmented following METH sensitization, as observed in WT mice. These data indicate that AC 1/8 are critical to mechanisms subserving drug‐induced behavioral sensitization and mediate nigrostriatal pathway METH sensitivity. [Image: see text]Calcium/calmodulin‐stimulated adenylyl cyclase (AC) isoforms 1 and 8 were studied for their involvement in the adaptive neurobehavioral responses to methamphetamine. AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine‐induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP‐32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3‐MT, 3‐methoxytyramine; Ca(2+), calcium; CaM, calmodulin; cdk5; cyclin‐dependent kinase 5; DA, dopamine; DARPP‐32, dopamine‐ and cAMP‐regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A.
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spelling pubmed-50494862016-10-06 Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice Bosse, Kelly E. Charlton, Jennifer L. Susick, Laura L. Newman, Brooke Eagle, Andrew L. Mathews, Tiffany A. Perrine, Shane A. Conti, Alana C. J Neurochem ORIGINAL ARTICLES The cAMP/protein kinase A pathway regulates methamphetamine (METH)‐induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) and striatal dopamine function were evaluated in mice lacking AC 1/8 (DKO) and wild‐type (WT) mice. Only 5 mg/kg METH induced an acute locomotor response in DKO mice, which was significantly attenuated versus WT controls. DKO mice showed a marked attenuation in the development and expression of METH‐induced behavioral sensitization across doses relative to WT controls. While basal and acute METH (5 mg/kg)‐evoked accumbal dialysate dopamine levels were similar between genotypes, saline‐treated DKO mice showed elevated tissue content of dopamine and homovanillic acid in the dorsal striatum (DS), reflecting dysregulated dopamine homeostasis and/or metabolism. Significant reductions in DS dopamine levels were observed in METH‐sensitized DKO mice compared to saline‐treated controls, an effect not observed in WT mice. Notably, saline‐treated DKO mice had significantly increased phosphorylated Dopamine‐ and cAMP‐regulated phosphoprotein levels, which were not further augmented following METH sensitization, as observed in WT mice. These data indicate that AC 1/8 are critical to mechanisms subserving drug‐induced behavioral sensitization and mediate nigrostriatal pathway METH sensitivity. [Image: see text]Calcium/calmodulin‐stimulated adenylyl cyclase (AC) isoforms 1 and 8 were studied for their involvement in the adaptive neurobehavioral responses to methamphetamine. AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine‐induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP‐32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3‐MT, 3‐methoxytyramine; Ca(2+), calcium; CaM, calmodulin; cdk5; cyclin‐dependent kinase 5; DA, dopamine; DARPP‐32, dopamine‐ and cAMP‐regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A. John Wiley and Sons Inc. 2015-09-10 2015-12 /pmc/articles/PMC5049486/ /pubmed/26146906 http://dx.doi.org/10.1111/jnc.13235 Text en © 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle ORIGINAL ARTICLES
Bosse, Kelly E.
Charlton, Jennifer L.
Susick, Laura L.
Newman, Brooke
Eagle, Andrew L.
Mathews, Tiffany A.
Perrine, Shane A.
Conti, Alana C.
Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title_full Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title_fullStr Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title_full_unstemmed Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title_short Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
title_sort deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8‐deficient mice
topic ORIGINAL ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049486/
https://www.ncbi.nlm.nih.gov/pubmed/26146906
http://dx.doi.org/10.1111/jnc.13235
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